Treating Helicobacter pylori and Recurrent Clostridioides difficile Coinfection: A Delicate Balance in Management and a Need for Guidelines

ABSTRACT Treating Helicobacter pylori and Clostridioides difficile coinfection presents a challenging clinical dilemma. Treating H. pylori may increase the risk of C. difficile, and antibiotics generally have been shown to increase the risk of C. difficile infection/recurrence. While it may be reasonable to delay H. pylori treatment, this is especially challenging when there is an acute indication to treat H. pylori such as peptic ulceration or bleeding. There are no guidelines on the management of H. pylori and C. difficile coinfection. We report a patient who had H. pylori and recurrent C. difficile coinfection and suggest a management algorithm based on literature review and our institutional experience. Our patient received quadruple therapy for H. pylori along with vancomycin prophylaxis, taper, and a dose of bezlotoxumab and experienced good outcomes with resolution of his gastrointestinal bleeding and diarrhea.


INTRODUCTION
Since the cytopathic involvement of Clostridioides difficile in pseudomembranous colitis was first reported in 1978, the incidence and severity of C. difficile infection (CDI) have been topics of active research. 1Complications of CDI can be severe including toxic megacolon, bowel perforation, and death, emphasizing the need for appropriate and timely management.Soon after the implications of CDI were reported, the role of Helicobacter Pylori (H.pylori) in gastroduodenal ulcers and gastric cancers was demonstrated in 1982, and it was identified as the most common bacterial infection in humans, affecting about 50% of the world's population. 2,3omplications of H. pylori infection include gastritis, peptic ulcer disease, and gastric cancers.
Despite how commonplace C. difficile and H. pylori infections are, a true coinfection rate of these bacteria is unknown.However, C. difficile colitis occurring as a complication of H. pylori eradication therapy has been reported in the literature. 4,5Treating H. pylori and C. difficile coinfection presents a challenging clinical dilemma.Patient outcomes in CDI after eradication therapy have ranged from total resolution of symptoms to fulminant colitis. 6While it may be reasonable to delay H. pylori treatment to avoid the risk of worsening CDI, this is especially challenging when there is an acute indication to treat H. pylori such as peptic ulceration or bleeding.Despite the scarcity of reported coinfections, an established treatment guideline is necessary for appropriate intervention to mitigate the risk of complications from either bacteria.We report a patient who had recurrent C. difficile and H. pylori coinfection and suggest an evidence-based management algorithm.

CASE REPORT
An 80-year-old man with a history of perforated duodenal ulcer, surgically repaired 2 years ago, and recent C. difficile colitis with failure of treatment response to fidaxomicin and incomplete vancomycin course, presented with a 10-day history of 5 episodes of watery diarrhea per day.He was initially admitted to the intensive care unit for hypovolemic shock.C. difficile polymerase chain reaction (PCR) and toxin were positive, and he completed a 10-day vancomycin course.His symptoms improved, and repeat C. difficile PCR and toxin were negative; however, diarrhea later recurred with positive C. difficile PCR.Infectious stool studies were otherwise negative.He was diagnosed with recurrent C. difficile colitis and given bezlotoxumab and a vancomycin taper with plans to treat for 6-8 weeks.His hospital course was complicated by acute on chronic anemia requiring blood transfusions and prompting esophagogastroduodenoscopy, which revealed a 2 cm punched-out ulcer at the junction of the first and second portion of the duodenum with gastric biopsies showing H. pylori (Figure 1).Infectious disease was consulted, who advised delaying H. pylori treatment out of concern that antibiotics may worsen or prolong C. difficile colitis.The acute anemia subsequently worsened, which was deemed secondary to bleeding from the nonhealing duodenal ulcer, caused by untreated H. pylori.This prompted initiation of H. pylori quadrapole therapy with a 14-day course of tetracycline, metronidazole, bismuth, and omeprazole, and simultaneously switching vancomycin to prophylactic dosing (125 mg by mouth daily) while on H. pylori treatment instead of the previously recommended taper.After completing the 14-day H. pylori course, the vancomycin taper was resumed (125 mg by mouth 4 times a day for 14 days, then 125 mg by mouth twice a day for 7 days, then 125 mg by mouth daily for 7 days, and then 125 mg by mouth every other day for 14 days).The patient's diarrhea resolved without any complications, and his anemia stabilized.

DISCUSSION
We report a rare case of an 80-year-old man with recurrent C. difficile and H. pylori coinfection who experienced persistent bleeding prompting esophagogastroduodenoscopy and eradication of H. pylori using quadruple therapy while administering prophylactic C. difficile treatment with vancomycin and subsequent vancomycin taper.We suggest an evidence-based algorithm for managing such cases, which showed good outcomes in our patient.
Literature discussing management strategies for C. difficile and H. pylori coinfection consists of a few case reports.In the first case report, a patient presented with abdominal pain and diarrhea; the patient tested positive for coinfection and was  treated with vancomycin. 7However, after completion of treatment, he had recurrence CDI, for which he received fecal microbiota transplantation (FMT), observed for 1 month, and then underwent quadruple H. pylori eradication therapy with successful treatment of both infections.In the other case report, a patient with ulcerative colitis presented with weight loss and bloody diarrhea and tested positive for a coinfection.The decision was made to treat the C. difficile before H. pylori infection, to which the patient responded well. 8There are some limitations to the previously documented management strategies.In both reports, the patient did not experience acute complications from H. pylori that would otherwise prompt the need for acute management.Moreover, the unavailability of FMT for definitive treatment in recurrent C. difficile limits its utility.To date, FMT is inconsistently available in low-resource settings-the same settings in which many risk factors of C. difficile and H. pylori infections are prevalent. 9cording to our literature review and institutional experience, we propose a suggested algorithm for treating C. difficile and H. pylori coinfection based on disease and patient-specific characteristics (Figure 2).We based our approach on the Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) and American College of Gastroenterology guidelines. 10,11In our proposed coinfection treatment algorithm, we recommend quadruple therapy with metronidazole and tetracycline over triple therapy with clarithromycin and amoxicillin for H. pylori management.3][14] Regarding oral vancomycin for primary or secondary prophylaxis of CDI, mixed data have been reported.One systematic review and meta-analysis demonstrated that oral vancomycin was ineffective for primary prevention of CDI but was effective in secondary prevention of recurrent CDI. 15 Another systematic review and meta-analysis suggested that, in the setting of low-quality evidence, low-dose oral vancomycin prophylaxis can be used in select high-risk patients receiving systemic antibiotics associated with CDI. 16There is a need for large randomized clinical trials to clarify the utility of oral vancomycin prophylaxis for CDI.We also used bezlotoxumab which showed good outcomes aligning with prior literature of reducing risk of further recurrence in recurrent C. difficile cases. 17 conclusion, we suggest a management algorithm for treating H. pylori and C. difficile coinfection.This proposed algorithm stratifies CDI severity by mild to moderate and severe/ fulminant (Figure 2).H. pylori infection is then classified as with or without complications.If no H.pylori complications are present, we recommend treating the CDI first and considering C. difficile prophylaxis while subsequently treating the H. pylori infection in patients at high risk of C. difficile or in patients with severe C. difficile If H. pylori complications are present with a mild-to-moderate CDI, we recommend H. pylori treatment and prophylactic C. difficile treatment administered concurrently in patients at high risk of C. difficile In severe C. difficile cases with complicated H. pylori, we recommend case-specific management in accordance with institutional experience.When there is an acute indication to treat H. pylori, it may be beneficial to favor quadruple over triple therapy.Prophylaxis vancomycin until completing H. pylori treatment, followed by a vancomycin taper, showed good outcomes in our case of recurrent C. difficile.Future studies are needed to externally validate our approach and establish guidelines for managing H. pylori and C. difficile coinfection to prevent complications and improve outcomes.

Figure 1 .
Figure 1.Endoscopic image of a giant at least 2 cm punched-out ulcer at the junction of the first and second portions of the duodenum.

Figure 2 .
Figure 2. Suggested algorithm for treating Clostridioides difficile and Helicobacter pylori coinfection based on disease and patient-specific characteristics, literature review, and our institution experience.